Effects of Smoking and Cessation on Subclinical Arterial Disease: A Substudy of a Randomized Controlled Trial

The mechanisms by which smoking cessation reduces cardiovascular disease risk are unclear. We evaluated longitudinal changes in carotid intima-media thickness among current smokers enrolled in a prospective, randomized smoking cessation clinical trial.Subjects were enrolled in a randomized, double-blind, placebo-controlled trial of 5 smoking cessation pharmacotherapies and underwent carotid ultrasonography with carotid intima-media thickness measurement. Subjects were classified as continuously abstinent (biochemically confirmed abstinence at 6 months, 1 year, and 3 years post-quit attempt), intermittently abstinent (reported smoking at one of the three time points), or smoked continuously (reported smoking at all three time points). The primary endpoint was the absolute change (mm) in carotid intima-media thickness (ΔCIMT(max)) before randomization and 3 years after the target quit date. Pearson correlations were calculated and multivariable regression models (controlling for baseline CIMT(max) and research site) were analyzed. Among 795 subjects (45.2 ± 10.6 years old, 58.5% female), 189 (23.8%) were continuously abstinent, 373 (46.9%) smoked continuously, and 233 (29.3%) were abstinent intermittently. There was a greater increase in carotid intima-media thickness among subjects who were continuously abstinent than among those who smoked continuously (p = 0.020), but not intermittently (p = 0.310). Antihypertensive medication use (p = 0.001) and research site (p<0.001) independently predicted ΔCIMTmax--not smoking status. The greatest increase in carotid intima-media thickness among continuous abstainers was related to increases in body-mass index (p = 0.043).Smoking status did not independently predict ΔCIMT(max); increasing body-mass index and antihypertensive medication use were the most important independent predictors. The rapid reduction in cardiovascular disease events observed with smoking cessation is unlikely to be mediated by changes in subclinical atherosclerosis burden.ClinicalTrials.gov NCT00332644

Experience developing national evidence-based clinical guidelines for childhood pneumonia in a low-income setting - making the GRADE?

BACKGROUND: The development of evidence-based clinical practice guidelines has gained wide acceptance in high-income countries and reputable international organizations. Whereas this approach may be a desirable standard, challenges remain in low-income settings with limited capacity and resources for evidence synthesis and guideline development. We present our experience using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for the recent revision of the Kenyan pediatric clinical guidelines focusing on antibiotic treatment of pneumonia. METHODS: A team of health professionals, many with minimal prior experience conducting systematic reviews, carried out evidence synthesis for structured clinical questions. Summaries were compiled and distributed to a panel of clinicians, academicians and policy-makers to generate recommendations based on best available research evidence and locally-relevant contextual factors. RESULTS: We reviewed six eligible articles on non-severe and 13 on severe/very severe pneumonia. Moderate quality evidence suggesting similar clinical outcomes comparing amoxicillin and cotrimoxazole for non-severe pneumonia received a strong recommendation against adopting amoxicillin. The panel voted strongly against amoxicillin for severe pneumonia over benzyl penicillin despite moderate quality evidence suggesting clinical equivalence between the two and additional factors favoring amoxicillin. Very low quality evidence suggesting ceftriaxone was as effective as the standard benzyl penicillin plus gentamicin for very severe pneumonia received a strong recommendation supporting the standard treatment. CONCLUSIONS: Although this exercise may have fallen short of the rigorous requirements recommended by the developers of GRADE, it was arguably an improvement on previous attempts at guideline development in low-income countries and offers valuable lessons for future similar exercises where resources and locally-generated evidence are scarce

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency &gt;3%, and were also present in the mutant library, had fitness levels that were &gt;40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Imaging of the urinary tract: the role of CT and MRI

Computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly valuable tools for assessing the urinary tract in adults and children. However, their imaging capabilities, while overlapping in some respects, should be considered as complementary, as each technique offers specific advantages and disadvantages both in actual inherent qualities of the technique and in specific patients and with a specific diagnostic question. The use of CT and MRI should therefore be tailored to the patient and the clinical question. For the scope of this article, the advantages and disadvantages of these techniques in children will be considered; different considerations will apply in adult practice

Reproducibility of volumetric intravascular ultrasound radiofrequency-based analysis of coronary plaque composition in vivo

Intravascular ultrasound radiofrequency (RF-IVUS) data permit the analysis of coronary plaque composition in vivo and is used as an endpoint of ongoing pharmacological intervention trials. We assessed the reproducibility of volumetric RF-IVUS analyses in mild-to-moderately diseased atherosclerotic human coronary arteries in vivo. A total of 9,212 IVUS analyses on cross-sectional IVUS frames was performed to evaluate the reproducibility of volumetric RF-IVUS measurements in 33 coronary segments with a length of 27 ± 7 mm. For vessel, lumen, and plaque + media volume the relative measurement differences (P = NS for all) were (A = intraobserver comparison, same pullback) −0.40 ± 1.0%; −0.48 ± 1.4%; −0.35 ± 1.6%, (B = intraobserver comparison, repeated pullback) −0.42 ± 1.2%; −0.52 ± 1.8%; −0.43 ± 4.5% (C = interobserver comparison, same pullback) 0.71 ± 1.8%; 0.71 ± 2.2%, and 0.89 ± 5.0%, respectively. For fibrous, fibro-lipidic, calcium, and necrotic-core volumes the relative measurement differences (P = NS for all) were (A) 0.45 ± 2.1%; −1.12 ± 4.9%; −0.84 ± 2.1%; −0.22 ± 1.8%, (B) 1.40 ± 4.1%; 1.26 ± 6.7%; 2.66 ± 7.4%; 0.85 ± 4.4%, and (C) −1.60 ± 4.9%; 3.85 ± 8.2%; 1.66 ± 7.5%, and −1.58 ± 4.7%, respectively. Of note, necrotic-core volume showed on average the lowest measurement variability. Thus, in mild-to-moderate atherosclerotic coronary artery disease the reproducibility of volumetric compositional RF-IVUS measurements from the same pullback is relatively high, but lower than the reproducibility of geometrical IVUS measurements. Measurements from repeated pullbacks and by different observers show acceptable reproducibilities; the volumetric measurement of the necrotic-core shows on average the highest reproducibility of the compositional RF-IVUS measurement

Diffractive Dijet Production at sqrt(s)=630 and 1800 GeV at the Fermilab Tevatron

We report a measurement of the diffractive structure function $F_{jj}^D$ of the antiproton obtained from a study of dijet events produced in association with a leading antiproton in $\bar pp$ collisions at $\sqrt s=630$ GeV at the Fermilab Tevatron. The ratio of $F_{jj}^D$ at $\sqrt s=630$ GeV to $F_{jj}^D$ obtained from a similar measurement at $\sqrt s=1800$ GeV is compared with expectations from QCD factorization and with theoretical predictions. We also report a measurement of the $\xi$ ($x$-Pomeron) and $\beta$ ($x$ of parton in Pomeron) dependence of $F_{jj}^D$ at $\sqrt s=1800$ GeV. In the region $0.035<\xi<0.095$, $|t|<1$ GeV$^2$ and $\beta<0.5$, $F_{jj}^D(\beta,\xi)$ is found to be of the form $\beta^{-1.0\pm 0.1} \xi^{-0.9\pm 0.1}$, which obeys $\beta$-$\xi$ factorization.Comment: LaTeX, 9 pages, Submitted to Phys. Rev. Letter

Search for lepton flavor violating decays of a heavy neutral particle in p-pbar collisions at root(s)=1.8 TeV

We report on a search for a high mass, narrow width particle that decays directly to e+mu, e+tau, or mu+tau. We use approximately 110 pb^-1 of data collected with the Collider Detector at Fermilab from 1992 to 1995. No evidence of lepton flavor violating decays is found. Limits are set on the production and decay of sneutrinos with R-parity violating interactions.Comment: Figure 2 fixed. Reference 4 fixed. Minor changes to tex

Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 ${pb}^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a $3+1+n$-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for $n$=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure

Impact of analyzing less image frames per segment for radiofrequency-based volumetric intravascular ultrasound measurements in mild-to-moderate coronary atherosclerosis

Volumetric radiofrequency-based intravascular ultrasound (RF–IVUS) data of coronary segments are increasingly used as endpoints in serial trials of novel anti-atherosclerotic therapies. In a relatively time-consuming process, vessel and lumen contours are defined; these contours are first automatically detected, then visually checked, and finally (in most cases) manually edited to generate reliable volumetric data of vessel geometry and plaque composition. Reduction in number of cross-sectional images for volumetric analysis could save analysis time but may also increase measurement variability of volumetric data. To assess whether a 50% reduction in number of frames per segment (every second frame) alters the reproducibility of volumetric measurements, we performed repeated RF–IVUS analyses of 15 coronary segments with mild-to-moderate atherosclerosis (20.2 ± 0.2 mm-long segments with 46 ± 13% plaque burden). Volumes were calculated based on a total of 731 image frames. Reducing the number of cross-sectional image frames for volumetric measurements saved analysis time (38 ± 9 vs. 68 ± 17 min/segment; P < 0.0001) and resulted for only a few parameters in (borderline) significant but mild differences versus measurements based on all frames (fibrous volume, P < 0.05; necrotic-core volume, P = 0.07). Compared to the intra-observer variability, there was a mild increase in measurement variability for most geometrical and compositional volumetric RF–IVUS parameters. In RF–IVUS studies of mild-to-moderate coronary disease, analyzing less image frames saved analysis time, left most volumetric parameters greatly unaffected, and resulted in a no more than mild increase in measurement variability of volumetric data

Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron

We have measured the number of like-sign (LS) and opposite-sign (OS) lepton pairs arising from double semileptonic decays of $b$ and $\bar{b}$-hadrons, pair-produced at the Fermilab Tevatron collider. The data samples were collected with the Collider Detector at Fermilab (CDF) during the 1992-1995 collider run by triggering on the existence of $\mu \mu$ and $e \mu$ candidates in an event. The observed ratio of LS to OS dileptons leads to a measurement of the average time-integrated mixing probability of all produced $b$-flavored hadrons which decay weakly, $\bar{\chi} = 0.152 \pm 0.007$ (stat.) $\pm 0.011$ (syst.), that is significantly larger than the world average $\bar{\chi} = 0.118 \pm 0.005$.Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.